Cancer remains a formidable disease with a high mortality rate in today""s society. Indeed, cancer is second only to cardiovascular disease as a cause of death, killing one out of four people in developed countries.
Cancerous tumors commonly originate from normal cells which transform into malignant cells or tumors. The initial tumor growth may be slow and thus may be difficult to detect. The growth often becomes more aggressive and invasive with time, eventually spreading throughout the whole body and resulting in death.
Photodynamic therapy (PDT) is one of the methods for treating tumors. For review, see Dougherty, T. J. Photochem. Photobiol. 1993, 58, 895. At present, the most commonly used sensitizers for clinical PDT practices are Photofrin II, an enriched active fraction of hematoporphyrin derivatives, and disulfonated aluminum phthalocyanine. These compounds, once photoactivated, induce severe oxidative damage to the structure of lipids, proteins, and nucleic acids. Since many biologically active molecules, e.g., DNA, demonstrate higher affinity toward stereospecific ligands, it is therefore desirable to develop stereospecific PDT sensitizers to enhance cytotoxicity of such antitumor agents.
An aspect of this invention relates to a compound of formula (I): 
Ff is F(xe2x80x94K)m(xe2x80x94Yxe2x80x94Z)q. F is a fullerene core. Each K, independently, is xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2,
xe2x80x94NHOH, xe2x80x94SO3H, xe2x80x94OSO3H, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CONHNH2, xe2x80x94P(OH)3, xe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2xe2x80x94NH3+, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2xe2x80x94N+(CH3)3, -glycoside, xe2x80x94OCH3, xe2x80x94OCH2(CHOH)4xe2x80x94CH2OH, xe2x80x94OCH2(CHOH)2xe2x80x94CH2OH, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94[CH(CO2H)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94[CH(CO2Ra)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94[C(CH3)(CO2H)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94[C(CH3)(CO2Ra)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94N(OH)2, xe2x80x94NH3+, xe2x80x94N+H2Ra, xe2x80x94N+HRaRb, or xe2x80x94N+RaRbRc. Each Y is xe2x80x94Axe2x80x94Bxe2x80x94, in which A is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94, or xe2x80x94NHxe2x80x94COxe2x80x94; and B is xe2x80x94Raxe2x80x94Oxe2x80x94[Si(CH3)2xe2x80x94Oxe2x80x94]1-100, C1-2000 alkyl, C6-40 aryl, C7-2000 alkylaryl, C7-2000 arylalkyl, (C1-30 alkyl ether),1-100, (C6-40 aryl ether)1-100, (C7-2000 alkylaryl ether)1-100, (C7-2000 arylalkyl ether)1-100, (C1-30 alkyl thioether)1-100,(C6-40 aryl thioether)1-100, (C7-2000 alkylaryl thioether)1-100, (C7-2000 arylalkyl thioether)1-100, (C2-50 alkyl ester)1-100, (C7-2000 aryl ester)1-100, (C8-2000 alkylaryl ester)1-100, (C8-2000 arylalkyl ester)1-100,xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether)1-100, xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C6-40 aryl ether)1-100, xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C7-2000 alkylaryl ether)1-100, xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C7-2000 arylalkyl ether)1-100, (C4-50 alkyl urethane),1-100, (C14-60 aryl urethane)-1-100, (C10-2000 alkylaryl urethane)1-100, (C10-2000 arylalkyl urethane)1-100, (C5-50 alkyl urea)1-100, (C14-60 aryl urea)1-100, (C10-2000 alkylaryl urea)1-100, (C10-2000 arylalkyl urea)1-100, (C2-50 alkyl amide)1-100, (C7-60 aryl amide)1-100, (C8-2000 alkylaryl amide)1-100, C(8-2000 arylalkyl amide)1-100, (C3-30 alkyl anhydride)1-100, (C8-50 aryl anhydride)1-100, (C9-2000 alkylaryl anhydride)1-100, (C9-2000 arylalkyl anhydride)1-100, (C2-30 alkyl carbonate)1-100, (C7-50 aryl carbonate)1-100, (C8-2000 alkylaryl carbonate)1-100, (C8-2000 arylalkyl carbonate)1-100, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100xe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100xe2x80x94Rcxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100xe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100xe2x80x94Rcxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(C2-50 alkyl amide, C7-60 aryl amide, C8-2000 alkylaryl amide, or C8-2000 arylalkyl amide)1-100, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(2-50 alkyl amide, C7-60 aryl amide, C8-2000 alkylaryl amide, or C8-2000 arylalkyl amide)1-100, or a bond; each Z, independently, is xe2x80x94Gxe2x80x94D, wherein G is xe2x80x94Raxe2x80x94, xe2x80x94Raxe2x80x94Arxe2x80x94, xe2x80x94Arxe2x80x94Raxe2x80x94, or xe2x80x94Arxe2x80x94; and D is xe2x80x94H, xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHOH, xe2x80x94SO3H, xe2x80x94OSO3H, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CONHNH2, xe2x80x94CH(NH2)xe2x80x94CO2H, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94P(OH)3, xe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2NH3+, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2xe2x80x94N+(CH3)3, -glycoside, -oligosaccharide, xe2x80x94CO-glycoside, xe2x80x94CO-oligosaccharide, xe2x80x94OCH3, xe2x80x94OCH2(CHOH)4xe2x80x94CH2OH, xe2x80x94OCH2(CHOH)2xe2x80x94CH2OH, xe2x80x94COxe2x80x94OCH2(CHOH)4xe2x80x94CH2OH, xe2x80x94C6H3(OH)2, xe2x80x94N(CH2CO2H)2, xe2x80x94COxe2x80x94N(CH2CO2H)2, xe2x80x94COxe2x80x94NHxe2x80x94C(CH2CH2CO2H)3, xe2x80x94COxe2x80x94NHxe2x80x94C(CH2CH2OH)3, xe2x80x94[CH2xe2x80x94CH(CO2Ra)]1-100xe2x80x94H, xe2x80x94NH3+, xe2x80x94N+H2Ra, xe2x80x94N+HRaRb, or xe2x80x94N+RaRbRc. Each of Ra, Rb, and Rc, independently, is C1-20 alkyl and Ar is aryl, q is 0-30, and m is 0-30. Note that the sum of q and m is 0-30. Each of R1 and R4, independently, is xe2x95x90O or C1-20 hydrocarbon. A hydrocarbon is a moiety containing carbon and hydrogen, e.g., alkyl, alkenyl, or alkynyl. Each of R2 and R5, independently, is C1-20 hydrocarbon; wherein R1 and R2, or R4 and R5 can join together to form C6-40 aryl which is optionally substituted with halide, xe2x80x94OH, xe2x80x94NHNH2, xe2x80x94NH2OH, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94CH2xe2x80x94CH2xe2x80x94D, xe2x80x94CH2xe2x80x94Bxe2x80x94Z, xe2x80x94COxe2x80x94CH2xe2x80x94D, xe2x80x94COxe2x80x94Bxe2x80x94Z, xe2x80x94Oxe2x80x94Bxe2x80x94Z, or xe2x80x94NHxe2x80x94Bxe2x80x94Z. Each of R3 and R6, independently, is xe2x80x94H, xe2x80x94CH2xe2x80x94D, xe2x80x94Bxe2x80x94Z, xe2x80x94Gxe2x80x94E, xe2x80x94Gxe2x80x94COxe2x80x94E, or a side chain of an amino acid. E is E1, E2, or E3, in which E1 is Y1,Y2-amino, (Y1,Y2-alkyl)-amino, Y1,Y2-ethylenediamino, (dihydroxymethyl)alkylamino, (X1,X3-aryl)amino, or X1,X3-aryloxy; E2 is Y1,Y2-alkoxy, (Y1,Y2-amino)alkoxy, (Y1,Y2, Y3-aryl)oxy, (dihydroxyalkyl)-aryloxy, (Y1,Y2,Y3-alkyl)amino, (Y1,Y2,Y3-aryl)amino, dihydroxyalkylamino, Y1,Y2,Y3-alkoxy, (trihydroxyalkyl)alkoxy, (trihydroxyalkyl)alkylamino, (dicarboxyalkyl)amino, (Y1,Y2,Y3-alkyl)thio, (X1,X3-aryl)thio, (Y1,Y2-alkyl)thio, (dihydroxyalkyl)thio, Y1, Y2-dioxoalkyl, or tri-(Y1,Y2,Y3-methylaminocarboxyethyl)methylamino; and E3 is ((glycosidyl)oxoheteroaryl)amino, ((glycosidyl)oxoaryl)amino, (X1,X2,X3-heteroaryl)amino, (X1-diarylketone)amino, (X,X1-oxoaryl)amino, (X,X1-dioxoaryl)amino, (Y1-alkyl,Y2-alkyldioxoheteroaryl)amino, (Y1-alkyl,Y2-alkyldioxoaryl)amino, (di(Y1,Y2-methyl)dioxoheteroaryl)amino, (di(Y1,Y2-methyl)dioxoaryl)amino, ((glycosidyl)heteroaryl)amino, ((glycosidyl)aryl)amino, ((carboxylacetylalkyl)oxo-heteroaryl)amino, ((carboxylacetylalkyl)oxoaryl)amino, ((isopropylaminohydroxy-alkoxy)aryl)amino, (X1,X2,X3-alkylaryl)amino, (X1,X2,X3-heteroaryl)oxy, (isopropylaminohydroxyalkyl)aryloxy, (X1,X2,X3-oxoheteroaryl)oxy, (X1,X2,X3-oxoaryl)oxy, (X1,Y1-oxoheteroaryl)oxy, (X1-diarylketone)oxy, (X,X1-oxoaryl)oxy, (X1,X2-dioxoaryl)oxy, (Y1,Y2,di-aminodihydroxy)alkyl, (X1,X2-heteroaryl)thio, ((tricarboxylalkyl)ethylene-diamino)alkoxy, (X1,X2-oxoaryl)thio, (X1,X2-dioxoaryl)thio, (glycosidylheteroaryl)thio, (glycosidylaryl)thio, Y1-alkyl(thiocarbonyl)thio, Y1,Y2, -alkyl(thiocarbonyl)thio, Y1,Y2,Y3-alkyl(thiocarbonyl)thio, (Y1,Y2-aminothiocarbonyl)thio, (pyranosyl)thio, cysteinyl, tyrosinyl, (phenylalainyl)amino, (dicarboxyalkyl)thio, (aminoaryl)1-100amino, (pyranosyl)amino, (Y1-aminoaryl)1-100amino, (amino(sulfoaryl))1-100amino, peptidyl, thymidinyl, uridinyl, guanosinyl, adenosinyl, cholesteryl, or biotinylalkoxy. X is halide. Each of X1, X2, and X3, independently, is xe2x80x94Y1, xe2x80x94Oxe2x80x94Y1, xe2x80x94Sxe2x80x94Y1, xe2x80x94NHxe2x80x94Y1, xe2x80x94COxe2x80x94Oxe2x80x94Y1, xe2x80x94Oxe2x80x94COxe2x80x94Y1, xe2x80x94COxe2x80x94NHxe2x80x94Y1, xe2x80x94COxe2x80x94NY1Y2, xe2x80x94NHxe2x80x94COxe2x80x94Y1, xe2x80x94SO2xe2x80x94Y1, xe2x80x94CHY1Y2, or xe2x80x94NY1Y2. Each of Y1, Y2, and Y3, independently, is xe2x80x94Z or xe2x80x94Bxe2x80x94Z. Each of x and y, independently, is 0 or 1; and s is 1-6. Note that when x is 0, R1 is xe2x95x90O; that when y is 0, R4 is xe2x95x90O; that when x is 1, R1 and R2 join together to form C6-40 aryl; and that when y is 1, R4 and R5 join together to form C6-40 aryl.
Another aspect of this invention relates to a method for preparing a compound of formula (I). The method includes reacting a compound of formula (II): 
wherein M is a Cu, Mn, Fe, Co, Ni, Ru, Rh, Os, Zn, Cr, Ti, or Zr ion, with a fullerene compound Ff of the formula F(xe2x80x94K)m(xe2x80x94Yxe2x80x94Z)q wherein the sum of q and m is 0 to form a compound of formula (III): 
M is then removed from a compound of formula (III), e.g., by using an ion exchange resin such as Dowex, to form a compound of formula (I) wherein the sum of q and m is 0. The compound of formula (I) wherein the sum of q and m is 0 can be further treated with a nitrating or sulfating agent to form a nitrofullerene or cyclosulfated fullerene, and contacting the nitrofullerene or cyclosulfated fullerene with a nucleophilic agent to form a compound of formula (I) wherein the sum of q and m is greater than 0, i.e., a derivatized fulleropyrrolidine compound of this invention.
The compound of formula (II) can be prepared by reacting a compound of formula (IV): 
with a metal salt MX, wherein M is a Cu, Mn, Fe, Co, Ni, Ru, Rh, Os, Zn, Cr, Ti, or Zr ion, and X is an anion such as sulfate, halide, acetate, and nitrate. As to the compound of formula (IV), it is prepared by reacting a compound of formula (V): 
with a compound of formula (VI): 
Yet another aspect of this invention relates to a compound of formula (VII). 
Ff is F(xe2x80x94K)m(xe2x80x94Yxe2x80x94Z)q. F is a fullerene core. Each K, independently, is xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2,
xe2x80x94NHOH, xe2x80x94SO3H, xe2x80x94OSO3H, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CONHNH2, xe2x80x94P(OH)3, xe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2xe2x80x94NH3+, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2xe2x80x94N+(CH3)3, -glycoside, xe2x80x94OCH3, xe2x80x94OCH2(CHOH)4xe2x80x94CH2OH, xe2x80x94OCH2(CHOH)2xe2x80x94CH2OH, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94[CH(CO2H)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94[CH(CO2Ra)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94[C(CH3)(CO2H)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94[C(CH3)(CO2Ra)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94N(OH)2, xe2x80x94NH3+, xe2x80x94N+H2Ra, xe2x80x94N+HRaRb, or xe2x80x94N+RaRbRc. Each Y is xe2x80x94Axe2x80x94Bxe2x80x94, in which A is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94, or xe2x80x94NHxe2x80x94COxe2x80x94; and B is xe2x80x94Raxe2x80x94Oxe2x80x94[Si(CH3)2xe2x80x94Oxe2x80x94]1-100, C1-2000 alkyl, C6-40 aryl, C7-2000 alkylaryl, C7-2000 arylalkyl, (C1-30alkyl ether)1-100, (C6-40 aryl ether)1-100, (C7-2000 alkylaryl ether)1-100, (C7-2000 arylalkyl ether)1-100, (C1-30 alkyl thioether)1-100, (C6-40 aryl thioether)1-100, (C7-2000 alkylaryl thioether)1-100, (C7-2000 arylalkyl thioether)1-100, (C2-50 alkyl ester)1-100, (C7-2000 aryl ester)1-100, (C8-2000 alkylaryl ester)1-100, (C8-2000 arylalkyl ester)1-100, xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether)1-100, xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C6-40 aryl ether)1-100, xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C7-2000 alkylaryl ether)1-100, xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C7-2000 arylalkyl ether)1-100, (C4-50 alkyl urethane)1-100, (C14-60 aryl urethane)1-100, (C10-2000 alkylaryl urethane)1-100, (C10-2000 arylalkyl urethane)1-100, (C5-50 alkyl urea)1-100, (C14-60 aryl urea)1-100, (C10-2000 alkylaryl urea)1-100, (C10-2000 arylalkyl urea)1-100, (C2-50 alkyl amide)1-100, (C7-60 aryl amide)1-100, (C8-2000 alkylaryl amide)1-100, (C8-2000 arylalkyl amide)1-100, (C3-30 alkyl anhydride)1-100, (C8-50 aryl anhydride)1-100, (C9-2000 alkylaryl anhydride)1-100, (C9-2000 arylalkyl anhydride)1-100, (C2-30 alkyl carbonate)1-100, (C7-50 aryl carbonate)1-100, (C8-2000 alkylaryl carbonate)1-100, (C8-2000 arylalkyl carbonate)1-100, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100xe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100xe2x80x94Rcxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100xe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(C2-50 alkyl amide, C7-60 aryl amide, C8-2000 alkylaryl amide, or C8-2000 arylalkyl amide)1-100, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(C2-50 alkyl amide, C7-60 aryl amide, C8-2000 alkylaryl amide, or C8-2000 arylalkyl amide)1-100, or a bond; each Z, independently, is xe2x80x94Gxe2x80x94D, wherein G is xe2x80x94Raxe2x80x94, xe2x80x94Raxe2x80x94Arxe2x80x94, xe2x80x94Arxe2x80x94Raxe2x80x94, or xe2x80x94Arxe2x80x94; and D is xe2x80x94H, xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHOH, xe2x80x94SO3H, xe2x80x94OSO3H, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CONHNH2, xe2x80x94CH(NH2)xe2x80x94CO2H, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94P(OH)3, xe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2NH3+, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2xe2x80x94N+(CH3)3, -glycoside, -oligosaccharide, xe2x80x94CO-glycoside, xe2x80x94CO-oligosaccharide, xe2x80x94OCH3, xe2x80x94OCH2(CHOH)4xe2x80x94CH2OH, xe2x80x94OCH2(CHOH)2xe2x80x94CH2OH, xe2x80x94COxe2x80x94OCH2(CHOH)4xe2x80x94CH2OH, xe2x80x94C6H3(OH)2, xe2x80x94N(CH2CO2H)2, xe2x80x94COxe2x80x94N(CH2CO2H)2, xe2x80x94COxe2x80x94NHxe2x80x94C(CH2CH2CO2H)3, xe2x80x94COxe2x80x94NHxe2x80x94C(CH2CH2OH)3, xe2x80x94[CH2xe2x80x94CH(CO2Ra)]1-100xe2x80x94H, xe2x80x94NH3+, xe2x80x94N+H2Ra, xe2x80x94N+HRaRb, or xe2x80x94N+RaRbRc. Each of Ra, Rb, and Rc, independently, is C1-20 alkyl and Ar is aryl, q is 0-30, and m is 0-30. Note that the sum of q and m is 0-30. Each of R1 and R4, independently, is xe2x95x90O or C1-20 hydrocarbon. Each of R2 and R5, independently, is C1-20 hydrocarbon. R1 and R2, or R4 and R5 can join together to form C6-40 aryl which is optionally substituted with halide, xe2x80x94OH, xe2x80x94NHNH2, xe2x80x94NH2OH, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94CH2xe2x80x94CH2xe2x80x94D, xe2x80x94CH2xe2x80x94Bxe2x80x94Z, xe2x80x94COxe2x80x94CH2xe2x80x94D, xe2x80x94COxe2x80x94Bxe2x80x94Z, xe2x80x94Oxe2x80x94Bxe2x80x94Z, or xe2x80x94NHxe2x80x94Bxe2x80x94Z. Each of R3 and R6, independently, is xe2x80x94H, xe2x80x94CH2xe2x80x94D, xe2x80x94Bxe2x80x94Z, xe2x80x94Gxe2x80x94E, xe2x80x94Gxe2x80x94COxe2x80x94E or a side chain of an amino acid. Each of B, D, and Z having been defined above. E is E1, E2, or E3, in which E1 is Y1,Y2-amino, (Y1,Y2-alkyl)-amino, Y1,Y2-ethylenediamino, (dihydroxymethyl)-alkylamino, (X1,X3-aryl)amino, or X1,X3-aryloxy; E2 is Y1,Y2-alkoxy, (Y1,Y2-amino)alkoxy, (Y1,Y2,Y3-aryl)oxy, (dihydroxyalkyl)-aryloxy, (Y1,Y2,Y3-alkyl)amino, (Y1,Y2,Y3-aryl)amino, dihydroxyalkylamino, Y1,Y2,Y3-alkoxy, (trihydroxyalkyl)alkoxy, (trihydroxyalkyl)-alkylamino, (dicarboxyalkyl)amino, (Y1,Y2,Y3-alkyl)thio, (X1,X3-aryl)thio, (Y1,Y2-alkyl)thio, (dihydroxyalkyl)thio, Y1,Y2-dioxoalkyl, or tri-(Y1,Y2,Y3-methylaminocarboxyethyl)methylamino; and E3 is ((glycosidyl)oxoheteroaryl)amino, ((glycosidyl)oxoaryl)amino, (X1,X2,X3-heteroaryl)amino, (X1-diarylketone)amino, (X,X1-oxoaryl)amino, (X,X1-dioxoaryl)amino, (Y1-alkyl,Y2-alkyldioxoheteroaryl)amino, (Y1-alkyl,Y2-alkyldioxoaryl)amino, (di(Y1,Y2-methyl)dioxoheteroaryl)amino, (di(Y1,Y2-methyl)dioxoaryl)amino, ((glycosidyl)heteroaryl)amino, ((glycosidyl)aryl)amino, ((carboxylacetylalkyl)oxo-heteroaryl)amino, ((carboxylacetylalkyl)oxoaryl)amino, ((isopropylaminohydroxy-alkoxy)aryl)amino, (X1,X2,X3-alkylaryl)amino, (X1,X2,X3-heteroaryl)oxy, (isopropylaminohydroxyalkyl)aryloxy, (X1,X2,X3-oxoheteroaryl)oxy, (X1,X2,X3-oxoaryl)oxy, (X1,Y1-oxoheteroaryl)oxy, (X1-diarylketone)oxy, (X,X1-oxoaryl)oxy, (X1,X2-dioxoaryl)oxy, (Y1,Y2,di-aminodihydroxy)alkyl, (X1,X2-heteroaryl)thio, ((tricarboxylalkyl)ethylene-diamino)alkoxy, (X1,X2-oxoaryl)thio, (X1,X2-dioxoaryl)thio, (glycosidylheteroaryl)thio, (glycosidylaryl)thio, Y1-alkyl(thiocarbonyl)thio, Y1,Y2,-alkyl(thiocarbonyl)thio, Y1,Y2,Y3-alkyl(thiocarbonyl)thio, (Y1,Y2-aminothio-carbonyl)thio, (pyranosyl)thio, cysteinyl, tyrosinyl, (phenylalainyl)amino, (dicarboxyalkyl)thio, (aminoaryl)1-100amino, (pyranosyl)amino, (Y1-aminoaryl)1-100amino, (amino(sulfoaryl))1-100amino, peptidyl, thymidinyl, uridinyl, guanosinyl, adenosinyl, cholesteryl, or biotinylalkoxy. X is halide. Each of X1, X2, and X3, independently, is xe2x80x94Y1, xe2x80x94Oxe2x80x94Y1, xe2x80x94Sxe2x80x94Y1, xe2x80x94NHxe2x80x94Y1, xe2x80x94COxe2x80x94Oxe2x80x94Y1, xe2x80x94Oxe2x80x94COxe2x80x94Y1, xe2x80x94COxe2x80x94NHxe2x80x94Y1, xe2x80x94NY1Y2, xe2x80x94NHxe2x80x94COxe2x80x94Y1, xe2x80x94SO2xe2x80x94Y1, xe2x80x94CHY1Y2, or xe2x80x94NY1Y2. Each of Y1, Y2, and Y3, independently, is xe2x80x94Z or xe2x80x94Bxe2x80x94Z. R7 is xe2x80x94Rd or xe2x80x94Oxe2x80x94Re. Rd is xe2x80x94OH, xe2x80x94OM, xe2x80x94NHNH2, xe2x80x94NHOH, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94Oxe2x80x94Bxe2x80x94Z, xe2x80x94NHxe2x80x94Bxe2x80x94Z, xe2x80x94E, xe2x80x94Oxe2x80x94Gxe2x80x94E, xe2x80x94NHxe2x80x94Gxe2x80x94E, xe2x80x94Oxe2x80x94Gxe2x80x94COxe2x80x94E, or xe2x80x94NHxe2x80x94Gxe2x80x94COxe2x80x94E. M is Cu, Mn, Fe, Co, Ni, Ru, Rh, Os, Zn, Cr, Ti, or Zr ion. Re is xe2x80x94H, xe2x80x94CH2xe2x80x94CH2xe2x80x94D, xe2x80x94CH2xe2x80x94Bxe2x80x94Z, xe2x80x94CH2xe2x80x94Gxe2x80x94E, xe2x80x94CH2xe2x80x94Gxe2x80x94COxe2x80x94E, xe2x80x94COxe2x80x94CH2xe2x80x94D, xe2x80x94COxe2x80x94Bxe2x80x94Z, COxe2x80x94Gxe2x80x94E, or xe2x80x94COxe2x80x94Gxe2x80x94COxe2x80x94E. R8 is Re. R9 is xe2x80x94Oxe2x80x94 or a bond. R10 is xe2x80x94Rd or xe2x80x94Re. Each of x and y, independently, is 0 or 1; and p is 1-30. Note that when x is 0, R1 is xe2x95x90O, and R7 is xe2x80x94Rd; that when y is 0, R4 is xe2x95x90O, and R9 is a bond, and R10 is Rd; that when x is 1, R1 and R2 join together to form C6-40 aryl, and R7 is xe2x80x94Oxe2x80x94Re; and that when y is 1, R4 and R5 join together to form C6-40 aryl, R9 is xe2x80x94Oxe2x80x94, and R10 is xe2x80x94Re. In addition, when p is greater than 1, x is 0.
Still another aspect of this invention relates to a compound of formula (VIII): 
Ff is F(xe2x80x94K)m(xe2x80x94Yxe2x80x94Z)q. F is a fullerene core. Each K, independently, is xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2,
xe2x80x94NHOH, xe2x80x94SO3H, xe2x80x94OSO3H, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CONHNH2, xe2x80x94P(OH)3, xe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2xe2x80x94NH3+, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2xe2x80x94N+(CH3)3, -glycoside, xe2x80x94OCH3, xe2x80x94OCH2(CHOH)4xe2x80x94CH2OH, xe2x80x94OCH2(CHOH)2xe2x80x94CH2OH, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94[CH(CO2H)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94[CH(CO2Ra)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94[C(CH3)(CO2H)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94[C(CH3)(CO2Ra)xe2x80x94CH2]1-100xe2x80x94OH, xe2x80x94N(OH)2, xe2x80x94NH3+, xe2x80x94N+H2Ra, xe2x80x94N+HRaRb, or xe2x80x94N+RaRbRc; each Y is xe2x80x94Axe2x80x94Bxe2x80x94, in which A is xe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94COxe2x80x94NHxe2x80x94, or xe2x80x94NHxe2x80x94COxe2x80x94. B is xe2x80x94Raxe2x80x94[Si(CH3)2xe2x80x94Oxe2x80x94]1-100, C1-2000 alkyl, C6-40 aryl, C7-2000 alkylaryl, C1-30 alkyl ether)1-100, (C6-40 aryl ether)1-100, (C7-2000 alkylaryl ether)1-100, (C7-2000 arylalkyl ether)1-100, (C1-30 alkyl thioether)1-100, (C6-40 aryl thioether)1-100, (C7-2000 alkylaryl thioether)1-100, (C7-2000 arylalkyl thioether)1-100, (C2-50 alkyl ester)1-100, (C7-2000 aryl ester)1-100, (C8-2000 alkylaryl ester)1-100, (C8-2000 arylalkyl ester)1-100, xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether)1-100, xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C6-40 aryl ether)1-100, xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C7-2000 alkylaryl ether)1-100, xe2x80x94Raxe2x80x94COxe2x80x94Oxe2x80x94(C7-2000 arylalkyl ether)1-100, (C4-50 alkyl urethane)1-100, (C14-60 aryl urethane)1-100, (C10-2000 alkylaryl urethane)1-100, (C10-2000 arylalkyl urethane)1-100, (C5-50 alkyl urea),1-100, (C14-60 aryl urea)1-100, (C10-200 alkylaryl urea)1-100, (C10-2000 arylalkyl urea)1-100, (C2-50 alkyl amide)1-100, (C7-60 aryl amide)1-100, (C8-2000 alkylaryl amide)1-100, (C8-2000 arylalkyl amide)1-100, (C3-30 alkyl anhydride)1-100, (C8-50 aryl anhydride)1-100, (C9-2000 alkylaryl anhydride)1-100, (C9-2000 arylalkyl anhydride)1-100, (C2-30 alkyl carbonate)1-100, (C7-50 aryl carbonate)1-100, (C8-2000 alkylaryl carbonate)1-100, (C8-2000 arylalkyl carbonate)1-100, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100xe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100xe2x80x94Rcxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94RbAr)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C1-30 alkyl ether, C6-40 aryl ether, C7-2000 alkylaryl ether, or C7-2000 arylalkyl ether)1-100xe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94(C2-50 alkyl ester, C7-60 aryl ester, C8-2000 alkylaryl ester, or C8-2000 arylalkyl ester)1-100xe2x80x94Rcxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Raxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(C2-50 alkyl amide, C7-60 aryl amide, C8-2000 alkylaryl amide, or C8-2000 arylalkyl amide)1-100, xe2x80x94Raxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94(Rb or Arxe2x80x94Rbxe2x80x94Ar)xe2x80x94NH""COxe2x80x94NHxe2x80x94(C2-50 alkyl amide, C7-60 aryl amide, C8-2000 alkylaryl amide, or C8-2000 arylalkyl amide)1-100, or a bond. Each Z, independently, is xe2x80x94Gxe2x80x94D, wherein G is xe2x80x94Raxe2x80x94, xe2x80x94Raxe2x80x94Arxe2x80x94, xe2x80x94Arxe2x80x94Raxe2x80x94, or xe2x80x94Arxe2x80x94; and D is xe2x80x94H, xe2x80x94OH, xe2x80x94SH, xe2x80x94NH2, xe2x80x94NHOH, xe2x80x94SO3H, xe2x80x94OSO3H, xe2x80x94CO2H, xe2x80x94CONH2, xe2x80x94CONHNH2, xe2x80x94CH(2)xe2x80x94CO2H, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94P(OH)3, xe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(OH)xe2x80x94Oxe2x80x94PO(OH)2, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2NH3+, xe2x80x94Oxe2x80x94PO(Oxe2x88x92)xe2x80x94Oxe2x80x94CH2CH2xe2x80x94N+(CH3)3, -glycoside, -oligosaccharide, xe2x80x94CO-glycoside, xe2x80x94CO-oligosaccharide, xe2x80x94OCH3, xe2x80x94OCH2(CHOH)4xe2x80x94CH2OH, xe2x80x94OCH2(CHOH)2xe2x80x94CH2OH, xe2x80x94COxe2x80x94OCH2(CHOH)4xe2x80x94CH2OH, xe2x80x94C6H3(OH)2, xe2x80x94N(CH2CO2H)2, xe2x80x94COxe2x80x94N(CH2CO2H)2, xe2x80x94COxe2x80x94NHxe2x80x94C(CH2CH2CO2H)3, xe2x80x94COxe2x80x94NHxe2x80x94C(CH2CH2OH)3, xe2x80x94[CH2xe2x80x94CH(CO2Ra)]1-100xe2x80x94H, xe2x80x94NH3+, xe2x80x94N+H2Ra, xe2x80x94N+HRaRb, or xe2x80x94N+RaRbRc. Each of Ra, Rb, and Rc, independently, is C1-20 alkyl and Ar is aryl q is 0-30, and m is 0-30. Note that the sum of q and m is 0-30. Each of R1 and R4, independently, is xe2x95x90O or C1-20 hydrocarbon; and each of R2 and R5, independently, is C1-20 hydrocarbon. R1 and R2, or R4 and R5 can join together to form C6-40 aryl which is optionally substituted with halide, xe2x80x94OH, xe2x80x94NHNH2, xe2x80x94NH2OH, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94CH2xe2x80x94CH2xe2x80x94D, xe2x80x94CH2xe2x80x94Bxe2x80x94Z, xe2x80x94COxe2x80x94CH2xe2x80x94D, xe2x80x94COxe2x80x94Bxe2x80x94Z, xe2x80x94Oxe2x80x94Bxe2x80x94Z, or xe2x80x94NHxe2x80x94Bxe2x80x94Z. Each of R3 and R6, independently, is xe2x80x94H, xe2x80x94CH2xe2x80x94D, xe2x80x94Bxe2x80x94Z, xe2x80x94Gxe2x80x94E, xe2x80x94Gxe2x80x94COxe2x80x94E or a side chain of an amino acid. E is E1, E2, or E3, in which E1 is Y1,Y2-amino, (Y1,Y2-alkyl)-amino, Y1,Y2-ethylenediamino, (dihydroxymethyl)alkylamino, (X1,X3-aryl)amino, or X1,X3-aryloxy; E2 is Y1,Y2-alkoxy, (Y1,Y2-amino)alkoxy, (Y1,Y2,Y3-aryl)oxy, (dihydroxyalkyl)-aryloxy, (Y1,Y2,Y3-alkyl)amino, (Y1,Y2,Y3-aryl)amino, dihydroxyalkylamino, Y1,Y2,Y3-alkoxy, (trihydroxyalkyl)alkoxy, (trihydroxyalkyl)alkylamino, (dicarboxyalkyl)amino, (Y1,Y2,Y3-alkyl)thio, (X1,X3-aryl)thio, (Y1,Y2-alkyl)thio, (dihydroxyalkyl)thio, Y1,Y2-dioxoalkyl, or tri-(Y1,Y2,Y3-methylaminocarboxyethyl)methylamino; and E3 is ((glycosidyl)oxoheteroaryl)amino, ((glycosidyl)oxoaryl)amino, (X1,X2,X3-heteroaryl)amino, (X1-diarylketone)amino, (X,X1-oxoaryl)amino, (X,X1-dioxoaryl)amino, (Y1-alkyl,Y2-alkyldioxoheteroaryl)amino, (Y1-alkyl,Y2-alkyldioxoaryl)amino, (di(Y1,Y2-methyl)dioxoheteroaryl)amino, (di(Y1,Y2-methyl)dioxoaryl)amino, ((glycosidyl)heteroaryl)amino, ((glycosidyl)aryl)amino, ((carboxylacetylalkyl)oxo-heteroaryl)amino, ((carboxylacetylalkyl)oxoaryl)amino, ((isopropylaminohydroxy-alkoxy)aryl)amino, (X1,X2,X3-alkylaryl)amino, (X1,X2,X3-heteroaryl)oxy, (isopropylaminohydroxyalkyl)aryloxy, (X1,X2,X3-oxoheteroaryl)oxy, (X1,X2,X3-oxoaryl)oxy, (X1,Y1-oxoheteroaryl)oxy, (X1-diarylketone)oxy, (X,X1-oxoaryl)oxy, (X1,X2-dioxoaryl)oxy, (Y1,Y2,di-aminodihydroxy)alkyl, (X1,X2-heteroaryl)thio, ((tricarboxylalkyl)ethylene-diamino)alkoxy, (X1,X2-oxoaryl)thio, (X1,X2-dioxoaryl)thio, (glycosidylheteroaryl)thio, (glycosidylaryl)thio, Y1-alkyl(thiocarbonyl)thio, Y1,Y2,-alkyl(thiocarbonyl)thio, Y1,Y2,Y3-alkyl(thiocarbonyl)thio, (Y1,Y2-aminothiocarbonyl)thio, (pyranosyl)thio, cysteinyl, tyrosinyl, (phenylalainyl)amino, (dicarboxyalkyl)thio, (aminoaryl)1-100amino, (pyranosyl)amino, (Y1-aminoaryl)1-100amino, (amino(sulfoaryl))1-100amino, peptidyl, thymidinyl, uridinyl, guanosinyl, adenosinyl, cholesteryl, or biotinylalkoxy. X is halide. Each of X1, X2, and X3, independently, is xe2x80x94Y1, xe2x80x94Oxe2x80x94Y1, xe2x80x94Sxe2x80x94Y1, xe2x80x94NHxe2x80x94Y1, xe2x80x94COxe2x80x94Oxe2x80x94Y1, xe2x80x94Oxe2x80x94COxe2x80x94Y1, xe2x80x94COxe2x80x94NHxe2x80x94Y1xe2x80x94, xe2x80x94COxe2x80x94NY1Y2, xe2x80x94NHxe2x80x94COxe2x80x94Y1, xe2x80x94SO2xe2x80x94Y1, xe2x80x94CHY1Y2, or xe2x80x94NY1Y2. Each of Y1, Y2, and Y3, independently, is xe2x80x94Z or xe2x80x94Bxe2x80x94Z. R7 is xe2x80x94Rd or xe2x80x94Oxe2x80x94Re. Rd is xe2x80x94OH, xe2x80x94OM, xe2x80x94NHNH2, xe2x80x94NHOH, xe2x80x94NHxe2x80x94CH2xe2x80x94CO2H, xe2x80x94Oxe2x80x94Bxe2x80x94Z, xe2x80x94NHxe2x80x94Bxe2x80x94Z, xe2x80x94E, xe2x80x94Oxe2x80x94Gxe2x80x94E, xe2x80x94NHxe2x80x94Gxe2x80x94E, xe2x80x94Oxe2x80x94Gxe2x80x94COxe2x80x94E, or xe2x80x94NHxe2x80x94Gxe2x80x94COxe2x80x94E. M is Cu, Mn, Fe, Co, Ni, Ru, Rh, Os, Zn, Cr, Ti, or Zr ion. Re is xe2x80x94H, xe2x80x94CH2xe2x80x94CH2xe2x80x94D, xe2x80x94CH2xe2x80x94Bxe2x80x94Z, xe2x80x94CH2xe2x80x94Gxe2x80x94E, xe2x80x94CH2xe2x80x94Gxe2x80x94COxe2x80x94E, xe2x80x94COxe2x80x94CH2xe2x80x94D, xe2x80x94COxe2x80x94Bxe2x80x94Z, xe2x80x94COxe2x80x94Gxe2x80x94E, or xe2x80x94COxe2x80x94Gxe2x80x94COxe2x80x94E. R8 is Re. R9 is xe2x80x94Oxe2x80x94Rfxe2x80x94 or xe2x80x94Rgxe2x80x94. Rf is xe2x80x94COxe2x80x94Bxe2x80x94Gxe2x80x94Oxe2x80x94, xe2x80x94COxe2x80x94Bxe2x80x94Gxe2x80x94NHxe2x80x94, xe2x80x94COxe2x80x94Bxe2x80x94Gxe2x80x94COxe2x80x94Oxe2x80x94, or xe2x80x94COxe2x80x94Bxe2x80x94Gxe2x80x94COxe2x80x94NHxe2x80x94. Rg is xe2x80x94NHxe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Oxe2x80x94Bxe2x80x94Gxe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94Bxe2x80x94Gxe2x80x94Oxe2x80x94, xe2x80x94NHxe2x80x94Bxe2x80x94Gxe2x80x94Nxe2x80x94, xe2x80x94Oxe2x80x94COxe2x80x94Bxe2x80x94Gxe2x80x94COxe2x80x94Oxe2x80x94, or xe2x80x94NHxe2x80x94COxe2x80x94Bxe2x80x94Gxe2x80x94COxe2x80x94NHxe2x80x94. R10 is xe2x80x94H. Each of x and y, independently, is 0 or 1; and r is 1-100. Note that when x is 0, R1 is xe2x95x90O, and R7 is xe2x80x94Rd; that when y is 0, R4 is xe2x95x90O, and R9 is xe2x80x94Rg, and R10 is xe2x80x94H; that when x is 1, R1 and R2 join together to form C6-40 aryl, and R7 is xe2x80x94Oxe2x80x94Re; and that when y is 1, R4 and R5 join together to form C6-40 aryl, R9 is xe2x80x94Oxe2x80x94Rf, and R10 is xe2x80x94H. Further, when r is greater than 1, x is 0.
A salt of a compound of the present invention is also within the scope of this invention. For example, a salt can form between an amino moiety and an anion such as sulfate, pyrosulfate bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, or maleate.
As used herein, a fullerene core is C60, C61, C62, C63, C64, C65, C70, C76, C78, C82, C84, or C92, or La@Cn, Ho@Cn, Gd@Cn, or Er@Cn, in which n is 60, 74, or 82.
An amino acid is a molecule containing both an amino group and a carboxylic acid, e.g., alanine, aspartic acid, cysteine, glutamic acid, phenylalanine, halophenylalanine, hydroxyphenylalanine, glycine, histidine, isoleucine, lysine, leucine, methionine, asparagine, glytamine, arginine, serine, theronine, valine, tryptophan, tyrosine, 2-aminobutyric acid, halophenylalanine, cyclohexylalanine, citrulline, homocitrulline, homoserine, norleucine, norvaline, or ornithine. Side chain of an amino acid is the substituent that is bonded to the carbon atom adjacent to the carbonyl carbon, i.e., the -carbon atom. For example, the side chain of each of alanine and omithine is xe2x80x94CH3 and xe2x80x94(CH2)3NH2, respectively. A peptidyl is a peptide moiety containing 2-100amino acid residues.
By the term xe2x80x9calkylxe2x80x9d is meant a straight chain that contains 1-30 carbon atoms, or a branched hydrocarbon chain of 3-30 carbon atoms, or cyclic hydrocarbon groups containing 3-30 carbon atoms, or otherwise indicated. These alkyl groups may also contain one or more double bond or triple bond and the cyclic alkyl groups may contain one or more heteroatoms, which are, typically, nitrogen, oxygen, or sulfur. Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, amyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, pentadecyl, icosyl, allyl, 2-butenyl, 2-pentenyl, 3-hexenyl, 4-decenyl, 5-nonadecenyl, 2-butnyl, 3-octnyl, 5-octadecnyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, adamantyl, norbornyl, isobornyl, cyclopentyl-methyl, cyclohexylmethyl, 1- or 2-cyclohexylethyl, cyclo-pentenyl, cyclohexenyl, cycloheptenyl, cyclo-octenyl, tetra-hydrofuranyl, tetrahydropyranyl, piperidinyl, morpholino and pyrrolindinyl groups.
As used herein, the term xe2x80x9carylxe2x80x9d refers to C6-40 aromatic rings. These moieties may also be fused rings and can be fused with aryl or heteroaryl which is as defined below. Fused rings are rings that share a common carbonxe2x80x94carbon bond. Typically aryl groups include phenyl, naphthyl, biphenyl, indazolyl, phenanthryl, and anthracyl.
By the tern xe2x80x9cheteroarylxe2x80x9d in this disclosure is meant C6-40 aromatic rings that contain one or more heteroatoms as defined above. These moieties may also be fused rings. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidyl, furyl, pyrrolyl, thienyl, thiazolyl, oxazolyl, imidazolyl, coumarinyl, indolyl, benzofuranyl, benzthiazolyl, benzothienyl, and benzothiadiazolyl.
As used herein, the term xe2x80x9chalidexe2x80x9d is defined as fluoro, chloro, bromo, or iodo. The term xe2x80x9cnucleophilic agentxe2x80x9d is defined as an electron-rich species that donates electrons in a reaction. Examples of nucleophilic agents that can be employed in the preparation of derivatized fulleropyrrolidines include amine, phenol, alkoxide, organothiolate, carbanion, organoamide anion, thiol, amino acid, and thiol carbamate anion. Note that the just-mentioned nucleophilic agents can be unsubstituted or substituted with other functional groups. Examples of substituted nucleophilic agents include 1,4-naphthoquinonyl-amine, tyrosine, dihydroxypropylthiol, and the like.
The structures of many of the moieties mentioned above are shown below within the pair of parentheses following each of the moieties: alkyl ether (xe2x80x94Rxe2x80x94Oxe2x80x94), aryl ether (xe2x80x94Arxe2x80x94Oxe2x80x94), alkylaryl ether (xe2x80x94Rxe2x80x94Arxe2x80x94Oxe2x80x94), arylalkyl ether (xe2x80x94Arxe2x80x94Rxe2x80x94Oxe2x80x94), alkyl thioether (xe2x80x94Rxe2x80x94Sxe2x80x94), aryl thioether (xe2x80x94Arxe2x80x94Sxe2x80x94), alkylaryl thioether (xe2x80x94Rxe2x80x94Arxe2x80x94Sxe2x80x94), arylalkyl thioether (xe2x80x94Arxe2x80x94Rxe2x80x94Sxe2x80x94), alkyl ester (xe2x80x94Rxe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94Rxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94R1xe2x80x94COxe2x80x94Oxe2x80x94R2xe2x80x94Oxe2x80x94COxe2x80x94, or xe2x80x94Rxe2x80x94Oxe2x80x94COxe2x80x94R2xe2x80x94COxe2x80x94Oxe2x80x94), aryl ester (xe2x80x94Arxe2x80x94Oxe2x80x94COxe2x80x94, xe2x80x94Arxe2x80x94COxe2x80x94O, xe2x80x94Ar1xe2x80x94COxe2x80x94Oxe2x80x94Ar2xe2x80x94Oxe2x80x94COxe2x80x94, or xe2x80x94Ar1xe2x80x94Oxe2x80x94COxe2x80x94Ar2xe2x80x94COxe2x80x94Oxe2x80x94), alkylaryl ester (xe2x80x94Rxe2x80x94Arxe2x80x94Oxe2x80x94COxe2x80x94 or xe2x80x94Rxe2x80x94Arxe2x80x94COxe2x80x94Oxe2x80x94), arylalkyl ester (xe2x80x94Arxe2x80x94Rxe2x80x94Oxe2x80x94COxe2x80x94 or xe2x80x94Arxe2x80x94Rxe2x80x94COxe2x80x94Oxe2x80x94), alkyl urethane (xe2x80x94R1xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94R2xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94), aryl urethane (xe2x80x94Ar1xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94Ar2xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94), alkylaryl urethane (xe2x80x94R1xe2x80x94Arxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94R2xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Rxe2x80x94Ar1xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94Ar2xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, or xe2x80x94R1xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94Arxe2x80x94R2xe2x80x94Arxe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94), arylalkyl urethane (xe2x80x94Arxe2x80x94R1xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94R2xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, xe2x80x94Ar1xe2x80x94Rxe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94Ar2xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94, or xe2x80x94Ar1xe2x80x94Oxe2x80x94COxe2x80x94NHxe2x80x94Ar2xe2x80x94Rxe2x80x94Ar2xe2x80x94NHxe2x80x94COxe2x80x94Oxe2x80x94), alkyl urea (xe2x80x94R1xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94R2xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94), aryl urea (xe2x80x94Ar1xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94Ar2xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94), alkylaryl urea (xe2x80x94R1xe2x80x94Arxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94R2xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94Rxe2x80x94Ar1xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94Ar2xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, or xe2x80x94R1xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94Arxe2x80x94R2xe2x80x94Arxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94), arylalkyl urea (xe2x80x94Arxe2x80x94RIxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94R2xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, Ar1xe2x80x94Rxe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94Ar2xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94, or xe2x80x94Ar1xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94Ar2xe2x80x94Rxe2x80x94Ar2xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94), alkyl amide (xe2x80x94Rxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94Rxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94R1xe2x80x94COxe2x80x94NH-R2xe2x80x94NHxe2x80x94COxe2x80x94, or xe2x80x94R1xe2x80x94NHxe2x80x94COxe2x80x94R2xe2x80x94COxe2x80x94NHxe2x80x94), aryl amide (xe2x80x94Arxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94Arxe2x80x94COxe2x80x94NHxe2x80x94, xe2x80x94Ar1xe2x80x94COxe2x80x94NHxe2x80x94Ar2xe2x80x94NHxe2x80x94COxe2x80x94, or xe2x80x94Ar1xe2x80x94NHxe2x80x94COxe2x80x94Ar2xe2x80x94COxe2x80x94NHxe2x80x94), alkylaryl amide (xe2x80x94Rxe2x80x94Arxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94Rxe2x80x94COxe2x80x94NHxe2x80x94Arxe2x80x94NHxe2x80x94COxe2x80x94, or xe2x80x94Rxe2x80x94NHxe2x80x94COxe2x80x94Arxe2x80x94COxe2x80x94NHxe2x80x94), arylalkyl amide (xe2x80x94Arxe2x80x94Rxe2x80x94NHxe2x80x94COxe2x80x94, xe2x80x94Arxe2x80x94COxe2x80x94NHxe2x80x94Rxe2x80x94NHxe2x80x94COxe2x80x94, or xe2x80x94Arxe2x80x94NHxe2x80x94COxe2x80x94Rxe2x80x94Oxe2x80x94NHxe2x80x94), alkyl anhydride (xe2x80x94Rxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94), aryl anhydride (xe2x80x94Arxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94), alkylaryl anhydride (xe2x80x94Rxe2x80x94Arxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94 or xe2x80x94Rxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Arxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94), arylalkyl anhydride (xe2x80x94Arxe2x80x94Rxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94 or xe2x80x94Arxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94Rxe2x80x94COxe2x80x94Oxe2x80x94COxe2x80x94), alkyl carbonate (xe2x80x94Rxe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94), aryl carbonate (xe2x80x94Arxe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94), alkylaryl carbonate (xe2x80x94Rxe2x80x94Arxe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Rxe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Arxe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94), and arylalkyl carbonate (xe2x80x94Arxe2x80x94Rxe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94 or xe2x80x94Arxe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94Rxe2x80x94Oxe2x80x94COxe2x80x94Oxe2x80x94). Note that the di-substitution pattern on Ar can be para, meta, or ortho.
As will be discussed below, one can employ stereospecific compounds of this invention to treat patients suffering from cancer via photodynamic therapy. The stereospecific nature of these compounds allow specific interactions with many biologically active compounds, e.g., protein receptors. The compounds of this invention can also be used to develop chromatographic materials for purifying chiral molecules.
Other features and advantages of the present invention will be apparent from the following description of the preferred embodiments, and also from the appending claims.
The invention relates to sterospecific fullerene compounds, i.e., E-isomeric fulleropyrrolidine compounds, as well as polymers made of such E-isomeric compounds. Also disclosed are methods for preparing these E-isomeric compounds and E-isomeric fulleropyrrolidine polymers.
Methods of this invention allow an E-isomeric fulleropyrrolidine compound to be prepared directly, thereby obviating the need to purifying a racemic mixture of both E- and Z-isomers. Separation of optical isomers is generally very difficult due to the close physical properties of optical isomers. Specifically, the methods described herein utilize a key starting material, i.e., a bicyclic imine-containing organometallic compound such as N-pyruvylidenealaninatoaquocopper (II). This bicyclic imine-containing compound, which is formed of two difunctional compounds, effects a stereospecific cycloaddition reaction when reacts with a fullerene core, e.g., C60, C76, or Gd@C82, thus forming only one fullerene isomer, i.e., the E-isomer.
Scheme I below illustrates a method for preparing an E-isomeric fulleropyrrolidine compound of this invention wherein its two carboxylic acid moieties are substituted at the same side of the pyrrolidine moiety. In the first step, an amino acid (H2Nxe2x80x94CH(Rb)xe2x80x94COOH) and a pyruvic acid derivative (Rbxe2x80x94C(xe2x95x90O)xe2x80x94COOH) are used as exemplary difunctional compounds which react with each other to form a bicyclic imine-containing copper (II) complex in the presence of copper (II) acetate. See step (i). Note that the coordination of the two carboxylic acid moieties with the copper (II) ion restricts rotations of the Nxe2x80x94C bond with respect to the Nxe2x95x90C bond, thus forcing the two carboxylic acid to be at the same side of the pyrrolidine that is formed between the imine moiety, i.e., xe2x80x94Cxe2x95x90NCxe2x80x94, of the copper complex and a double bond of a fullerene core, e.g., C60, via a cycloaddition reaction. See step (ii). Not only does the copper (II) ion enables only one stereospecific isomer, i.e., the E-isomer, to be formed, it also prevents thermal decarboxylation after dicarboxylic acid substituted fulleropyrrolidines are formed. By exchanging the copper (II) ion with the proton on a Dowex resin (H+ form), the corresponding E-isomeric dicarboxylic acid substituted fulleropyrrolidine product was isolated in a high yield ( greater than 85%). See Example 1 below. 
Scheme II below illustrates a method for preparing an E-isomeric fulleropyrrolidine compound of this invention wherein it is substituted with a carboxylic acid and an aromatic ring at the same side of the pyrrolidine moiety. The only difference between the methods shown in Scheme I and Scheme II lies in that the former method employs a difunctional carboxylic acid, e.g., 2-ketoglutaric acid, whereas the latter method employs a difunctional phenol, e.g., salicylaldehyde. The difunctional phenol, e.g., a carbonyl-containing phenol, can then react with a difunctional carboxylic acid, e.g., an amino acid, in the presence of a metal salt, e.g., Cu(OAc)2 or CoCl2, to form a bicyclic imine-containing metal complex. See step (i). The next two steps of the method, i.e., cycloaddition (step (ii)) and removal of metal ions (step (iii)), are identical to those described above. See Example 7 below. 
Alternatively, the bicyclic imine-containing organometallic compound can also be formed between an amine-containing phenol, e.g., 2xe2x80x2-aminoacetophenone, and a carbonyl-containing carboxylic acid, e.g., pyruvic acid, or a carbonyl-containing phenol, e.g., salicylaldehyde.
The resulting E-isomeric fulleropyrrolidine compound of formula (I) can be further derivatized, e.g., by attaching thereto a methylglucoside, by various known methods. See, e.g., U.S. Pat. No. 6,020,523. For example, the fulleropyrrolidine compound can be treated with a nitrating agent or a sulfating agent to form a nitrofulleropyrrolidine or a cyclosulfated-fulleropyrrolidine intermediate, which can then be converted into a derivatized E-isomeric fulleropyrrolidine by reacting with a nucleophilic agent. Examples of a nitrating agent include sodium nitrite and concentrated HNO3, dinitrogen tetraoxide, nitrogen dioxide, and fuming nitric acid. Cyclosulfated fullerene intermediates, on the other hand, can be formed by treating the fullerene with neat fuming sulfuric acid in the presence of an oxidant (e.g., P2O5, V2O5, or ScO2). Examples of a nucleophilic agent include primary and secondary organoamino compound, alkoxide, organothiolate, organophenol compound, carbanion, organoamide anion, thiocarbamate ion, and the like.
The E-isomeric fulleropyrrolidine compound of formula (I) can further react with each other to form a polymer (or an oligomer). The polymer formed can be a homopolymer or a copolymer, e.g., a random, a block, or a branched copolymer. Since a compound of formula (I) contains three termini, i.e., a pyrrolidine nitrogen ring atom and two carboxylic acid moieties (or a carboxylic moiety and a phenol hydroxy group, or two phenol hydroxyl groups), a number of polymers can be prepared via different linkages. Take a fullero-pyrrolidine compound containing two carboxylic acid moieties as an example, a polymer can be formed by linking the N-terminus (i.e., the pyrrolidine nitrogen ring atom) of a first compound of formula (I) to the C-terminus (i.e., one of the two carboxylic acid moieties) of a second compound of formula (I), and the N-terminus of this second compound of formula (I) can in turn be linked to the C-terminus of a third compound of formula (I), and so on. This polymer design is similar to that of a peptide. The just-described polymer, i.e., a polymer of formula (VII), supra, can be prepared by forming an internal anhydride between the two carboxylic acid moieties, which is then treated with a base such as 1,8-diazabicyclo-[5.4.0]undec-7-ene (DBU) to effect the polymerization reaction. Due to the highly reactive nature of the anhydride moiety, derivatization of the fullerene should be done after the polymerization step. See Scheme III and Example 11 below. 
A polymer of formula (VII) can also be prepared using a fulleropyrrolidine compound having a phenol and a carboxylic acid moiety. Since this compound (or monomer) contains one carboxylic acid and one amino group, polymerization can be effected by using common peptide coupling reagents, e.g., dicyclohexylcarbodiimide (DCC), benzotriazol-1-yloxytris(dimethylamino)-phosphonium hexafluorophosphate (BOP), or O-benzo-triazol-1-yl-N,N,Nxe2x80x2Nxe2x80x2-tetramethyluronium hexafluorophosphate (HBTU). Note that the hydroxy group of the phenol moiety may need to be protected, e.g., by silyl ethers, during polymerization.
Alternatively, a polymer of an E-isomeric fulleropyrrolidine compound of formula (I) can also be formed by linking the carboxylic acid moiety (or the hydroxy group of the phenol moiety) of one fulleropyrrolidine monomer to the carboxylic acid moiety of another fulleropyrrolidine monomer via a divalent linker, thus resulting in a polymer of formula (VIII). For example, a polyamide and a polyester can be formed by reacting a fulleropyrrolidine compound with two carboxylic acid moieties with a diamine (e.g., ethylenediamine) and a diol (e.g., 1,3-propanediol), respectively.
An E-isomeric fulleropyrrolidine compound of formula (I) can be used in photodynamic therapy (PDT) to treat patients suffering from cancer. See Example 16 below. The photo-induced cytotoxicity of a fullerene compound is connected with its ability to cleave DNA. Specifically, photogenerated triplet fullerene intermediate is involved in the energy transfer process which converts the ground-state triplet oxygen molecules into the excited molecular singlet oxygen 1O2. Singlet oxygen is capable of inducing DNA damage and degeneration of other tissues that lead to mutagenic effects on biological cells. The stereospecific nature of an E-isomeric fulleropyrrolidine compound of formula (I) can enhance its affinity to DNA which is in the form of a double helix. Polymers of formulas (VII) and (VIII), which contain a plurality of fulleropyrrolidine compounds of formula (I), can further enhance its biological activities by allowing delivery of multiple fullero-pyrrolidine compounds in a single molecule.
A pharmaceutical composition containing an effective amount of a fulleropyrrolidine compound of formula (I) (or a polymer formed therefrom) is also within the scope of this invention. The use of such a fulleropyrrolidine compound for the manufacture of a medicament for treating tumors is also within the scope of this invention. Still another aspect of this invention is a method for treating tumor by administering to a patient a pharmaceutical composition containing an effective amount of a fulleropyrrolidine compound of this invention. An effective amount is defined as the amount which is required to confer a therapeutic effect on the treated patient, and is typically determined based on age, surface area, weight, and condition of the patient. The interrelationship of dosages for animals and humans (based on milligrams per meter squared of body surface) is described by Freireich et al., Cancer Chemother. Rep. 1966, 50, 219. Body surface area may be approximately determined from height and weight of the patient. See, e.g., Scientific Tables, Geigy Pharmaceuticals, Ardley, N.Y., 1970, 537. An effective amount of a pyridyl cyanoguanidine compound of this invention can range from about 1 mg/kg to about 150 mg/kg (e.g., about 1 mg/kg to about 100 mg/kg). Effective doses will also vary, as recognized by those skilled in the art, dependant on route of administration, excipient usage, and the possibility of co-usage with other therapeutic treatments including use of other antitumor agents and radiation therapy.
The pharmaceutical composition may be administered via the parenteral route, including orally, topically, subcutaneously, intraperitoneally, intramuscularly, and intravenously. Examples of parenteral dosage forms include aqueous solutions of the active agent, in a isotonic saline, 5% glucose or other well-known pharmaceutically acceptable excipient. Solubilizing agents such as cyclodextrins, or other solubilizing agents well-known to those familiar with the art, can be utilized as pharmaceutical excipients for delivery of the therapeutic compounds.
A fulleropyrrolidine compound of this invention can be formulated into dosage forms for other routes of administration utilizing conventional methods. For example, it can be formulated in a capsule, a gel seal, or a tablet for oral administration. Capsules may contain any standard pharmaceutically acceptable materials such as gelatin or cellulose. Tablets may be formulated in accordance with conventional procedures by compressing mixtures of a pyridyl cyanoguanidine compound with a solid carrier and a lubricant. Examples of solid carriers include starch and sugar bentonite. The fulleropyrrolidine compound can also be administered in a form of a hard shell tablet or a capsule containing a binder, e.g., lactose or mannitol, a conventional filler, and a tableting agent.
Without further elaboration, it is believed that one skilled in the art can, based on the description herein, utilize the present invention to its fullest extent. The following specific examples are, therefore, to be construed as merely illustrative, and not limitative of the remainder of the disclosure in any way whatsoever. All publications recited herein, including patents, are hereby incorporated by reference in their entirety.